the ppt describes in detail the translational research and path of the drug from lab to bed side, CONSORT guidelines, DCGI guidelines, CTR-I, the GCP principles, medical ethics, sample size estimation for RCT, RCT designs including cross over design and factorial design, Randomized permuted blocks, blinding and matching.
2. Types of Studies
Epidemiological Studies
Observational
Descriptive Analytical
Interventional/ Experimental
RCT FieldTrial
Community
Trial
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3. Why ClinicalTrials?
Gold standard with aTotality of Evidence:
Lab Study- High Precision
Epidemiological Study- High Relevance
Designed to elucidate Most Appropriate Treatment for the
FUTURE PATIENTS
Should be done only in existence of CLINICAL EQUIPOISE
So, during enrollment the researcher must ensure Absence of
THERAPEUTIC MISCONCEPTION among the participants.
Also ensure the non-existence of Oxymoron: THERAPEUTIC
RESEARCH
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4. From Lab to Clinics to Community- the
Developmental Process Funnel
Drug
Discovery
Pre
clinical
Phase I
FIH
Phase II
POC
Phase III
Post
approval
Trials-
Phase IV
10,000
compounds
10- 15 yrs
$ 1 billion
1 compound
Bench to Bed SideTranslational Blocks
T0- Discovery Science T1 Phase
Clinical/Translational Research
NOT ClinicalTrial BorderlineTrial ClinicalTrial
T2 T3
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5. Pre Clinical Phase
Safety Testing- Toxicity and Physiological Response to the
new Compound is assessed
Organs targeted include:
Cardio- vascular
Neuro- muscular
Respiratory
+ Other Organs and systems depending on the compound’s action
Dose Dependence
Potential for Reversibility16-05-2014 5
6. Toxicity studies
AcuteToxicity: determine overdose effects
Repeated Dose Toxicity: maximum duration of
clinical trial
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7. MRSD Determination
HED= animal’s NOAEL (mg/kg)* Wt (Animal) 1-0.62
A 10 fold Safety margin is usually used, so:
MRSD= HED/ Safety factor
Maximum tolerated Dose (MTD) needs to be
estimated where the Dose limiting toxicity has a
certain probability
( )Wt (Human)
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9. Phase I- FIHTrial
Healthy volunteers are given a single dose in a
controlled environment (In- patient settings)
Volunteers usually paid
Risks are kept to be minimum
What needs to be assessed is:
Safety
Pharmacokinetics
Pharmacodynamics
Route and Rate of administration
Fixing up the end points
Physiologic effects in humans16-05-2014 10
10. POC Study
Patients having the disease of interest, are enrolled
Volunteers not paid
Moderate (or even serious) risks are acceptable
Done to assess:
The Dose response
Safety
Pathophysiology
Limited observation about efficacy
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11. Steps in Conducting a Phase III Clinical
Trial
Design Phase
Research Question- FINER Criteria, PICOT style
Study Designs
Ethical Considerations& GCP Guidelines
Registering with CTRI
Latest DGCA Guidelines-Video Record Every Consent
Sample Size, Clearly defined Inclusion- Exclusion
criteria
16-05-2014 12
12. Steps in Conducting a Phase III Clinical
Trial
Implementation Phase
Randomization v/s Random Allocation
Blinding
Control- StandardTreatment v/s Placebo
Monitoring& DSMB- InterimAnalysis
Analytical Phase
ITT v/s Per protocol analysis
CONSORT Guidelines
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13. Research Question
FINER; PICOT
Following need to be considered:
Effect Size
Composite endpoints
Surrogate End Points
Study duration
Secondary Questions
Sub group Hypothesis
Natural History Studies
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14. Study Designs
Two group parallel design-The Look ahead trial (T2DM obese
pts on Diabetes support& education v/s active, intensive
lifestyle modification)
Multi group parallel design-The Re-ly trial (Atr Fib pts on
warfarin v/s dabigatran 110mg v/s dabigatran 150 mg)
Factorial design-The SUPPORTTrial (very premature neonates
were randomized into Early surfactant v/s early CPAP and O2
Saturation 85% v/s 95%)
Cross over design- Pts can be compared on themselves. E.g.
Hemophilia trial. No carry over between the two treatment
periods- Rest period is needed16-05-2014 15
15. The History Behind Ethics
Nuremberg Code- 1946
Declaration of Helsinki- 1964
Council for International Organizations of
Medical SciencesCIOMS- 1982
International Conference on Harmonization
– Good clinical practice (ICH-GCP)- 1996
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16. Historical Perspectives
Council for International Organizations of Medical
Sciences (CIOMS) and WHO (1982) – International
ethical guidelines for biomedical research involving
human subjects
Revised – 1993, 2002
International Conference of Harmonization – Good
clinical practice (ICH-GCP)-1996)
International ethical and scientific quality standard for
designing, conducting, recording and reporting trials involving
human subjects.
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17. 13 Principles of GCP
1. Ethics (Declaration of Helsinki)
2. Risk Benefit analysis
3. Trial subjects (rights and safety)
4. Investigational product (Information support
study)
5. Scientifically sound
6. Compliance (IRB review)16-05-2014 19
18. 7. Qualified physician to provide medical care
8. Trial staff (trained in protocol)
9. Informed consent
10. Data (reporting, interpretation, verification)
11. Confidentiality
12. Good manufacturing practice of the
investigational product
13. QualityAssurance of all aspects of protocol
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19. 7 Components of the Ethics:
1. Social or Scientific value
2. ScientificValidity
3. Fair Subject Selection
4. Favorable risk- benefit ratio
5. Independent review
6. Informed Consent
7. Respect for potential and enrolled subjects
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20. Ethics in Trials
During Phase I Trials, 95% of the times,
participating patients do not benefit from theTrial
The probability (chance) of having any benefit 5%
Risk of fatal complication 5%
While there may be a significant chance of benefit in
Phase IIITrial
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23. Informed Consent - Elements
Information
Patient/subject information sheet
Comprehension
Simple and understandable language
Local language translations
Voluntariness
Consent
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24. Informed Consent
Community studies – Consent needed from
Community – group consent
Individuals
Children
Parent/guardian
Assent of child to his/her capability
Mentally Ill
Close biological relative
Legally authorized person
Certificate from psychiatrist
16-05-2014 28
25. Importance Of Clinical Trials Registration
To ensure transparency , accountability and to
increase public trust in the conduct of clinical
research.
Clinical trial registration and results reporting
would help ensure unbiased public records on
safety and efficacy of drugs.
All clinical trials should be registered before the
enrolment of the first patient and all results made
publicly available.
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26. Registration of Trials Globally
At the 58th WHA held on 25th May 2005 WHO had set up of an
International Clinical Trial Registry Platform (ICTRP), a one-stop
search portal for searching registers worldwide.
The ICTRP recommended 20 key points as Trial Registration
data Set that need to be publicly declared before the enrolment
of the first patient.
In the 59th General Assembly of the World Medical Association,
2008, in its revision of the Declaration of Helsinki among other
modifications, specifies that:
“Every clinical trial must be registered in a publicly accessible
database before recruitment of the first subject.”
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27. CTR- I
Till 2006, there was no national registry of clinical trials in
India
On July 20, 2007, ICMR through its National Institute of
Medical Statistics (NIMS) formed Clinical Trials Registry –
India (CTRI) www.ctri.nic.in with financial support from DST
andWHO.
The CTRI has additional data points over the ICTRP’s
recommended 20 point data set:
Later these additional points were borrowed from CTR- I and
were inculcated in the WHO’s ICTRP.
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28. Registration Data Set of the CTRI
1. Public Title of Study
2. Scientific Title of Study,
Acronym, if any
3. Secondary IDs, (UTN, Protocol
No etc)
4. Principal Investigator’s Name
and Address*
5. Contact Person (Scientific
Query)
6. Contact Person (Public Query)
7. Source/s of Material or Monetary
Support
8. Primary Sponsor
9. Secondary Sponsor
10. Countries of Recruitment
11. Site/s of study
12. Name of Ethics Committee and
approval status
13. Regulatory Clearance obtained
from DCGI
* Optional fields
14.Health Condition/Problem studied
15.Study Type
16.Intervention and Comparator agent
17.Key inclusion/Exclusion Criteria
18.Method of generating
randomization sequence*
19.Method of allocation concealment*
20.Blinding and masking*
21.Primary Outcome/s
22.Secondary Outcome/s
23.Target sample size
24.Phase of Trial
25.Date of first enrollment
26.Estimated duration of trial
27.Status of Trial
28.Publication details*
29.Brief Summary
Additional items of CTRI
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30. It is housed at the National Institute of Medical
Statistics, ICMR, New Delhi.
Trial registration is purely online, paperless
process and free of charge
The CTRI software application was modified and
implemented on 15th March 2011.
Clinical Trials Registry – India
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31. Objectives of CTRI
To establish a public record system by registering all
clinical trials on health products including:
Drugs
Devices
Vaccines
Herbal drugs
It makes the information available to both public and
healthcare professionals in an unbiased, scientific and timely
manner.
To create a complete, authentic and readily available
data of all ongoing and completed clinical trials.
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32. Objectives of CTRI
To provide a corrective system against “positive results
bias” and “selective reporting” of research results to peer
review publication.
To increase awareness and accountability of all the
participants of the clinical trials and also for public access:
Trial registration empowers the public and offer patients the choice
of enrolling in a clinical trial to gain access to latest breakthrough
treatment options.
To promote training, assistance and advocacy for clinical
trials by creating database and modules of study for
various aspects of clinical trials and its registration.
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33. Registration of clinical trials under
CTR- I is recommended by:
1. Drugs Controller General (India): Made
mandatory since June 2009
2. Editors of Indian Biomedical Journals;
3. Ethics Committees of various institutions,
AIIMS, CMC, Sir Ganga Ram Hospital etc.
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37. Registering Trials during PG Thesis
CTRI encourages registration of trials
being conducted as part of post-
graduation thesis work
This would help
Ensure ethical standards
Prevent unnecessary duplicate research
Raise the standard of research
Enable better exchange of data and ideas
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47. Analysis
Intent to treat
Modified Intent to treat
Per protocol Analysis
On assignedTt
Fully compliant with study domain
As treated Analysis
Best Active- Interventional
Compromised Observational
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48. Analysis to Study Outcome
Binary (HTN or Normotensive)
Measurable (BP reading)
Time to event (at what time during the follow up, has the
event occurred)
Other outcomes: No. of episodes (e.g. no of exaggeration
episodes of asthma, while on treatment)
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49. CONSORT (Con solidated S tandards o f
R eportingT rials) statement
Section/Topic Item
No
Checklist Reported
on Pg no
Title& Abstract 1a Identification as a randomised trial in the title
1b Structured summary of trial design, methods, results,
and conclusions (for specific guidance see CONSORT
for abstracts)
Introduction 2a Scientific background and explanation of rationale
Background&
Objectives
2b Specific objectives or hypotheses
Method
Trial Design 3a Description of trial design (such as parallel, factorial)
including allocation ratio
3b Important changes to methods after trial
commencement (such as eligibility criteria), with
reasons
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50. Section/Topic Item
No
Checklist Report
ed on
Pg no
Participants 4a Eligibility criteria for participants
4b Settings and locations where the data were collected
Interventions 5 The interventions for each group with sufficient
details to allow replication, including how and when
they were actually administered
outcomes 6a Completely defined pre-specified primary and
secondary outcome measures, including how and
when they were assessed
6b Any changes to trial outcomes after the trial
commenced, with reasons
Sample size 7a How sample size was determined
7b When applicable, explanation of any interim analyses
and stopping guidelines16-05-2014 64
51. Section/Topic Ite
m
No
Checklist Reported
on Pg no
Randomization
Sequence 8a Method used to generate the random allocation
sequence
Generation 8b Type of randomisation; details of any restriction (such as
blocking and block size)
Allocation
Concealment
mechanism
9 Mechanism used to implement the random allocation
sequence (such as sequentially numbered containers),
describing any steps taken to conceal the sequence until
interventions were assigned
Implementatio
n
10 Who generated the random allocation sequence, who
enrolled participants, and who assigned participants to
interventions
Blinding 11a If done, who was blinded after assignment to
interventions (for example, participants, care providers,
those assessing outcomes) and how
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52. Section/
Topic
Item
No
Checklist Reported
on Pg no
11b If relevant, description of the similarity of interventions
Statistical
Method
12a Statistical methods used to compare groups for primary
and secondary outcomes
12b Methods for additional analyses, such as subgroup
analyses and adjusted analyses
Results
Participants
(a flow
diagram
strongly
recommende
d)
13a For each group, the numbers of participants who were
randomly assigned, received intended treatment, and
were analysed for the primary outcome
13b For each group, losses and exclusions after
randomisation, together with reasons
Recruitment 14a Dates defining the periods of recruitment and follow-up
14b Why the trial ended or was stopped16-05-2014 66
53. Section/
Topic
Item
No
Checklist Reported
on Pg no
Baseline data 15 A table showing baseline demographic and clinical
characteristics for each group
Number
analyzed
16 For each group, number of participants (denominator)
included in each analysis and whether the analysis was
by original assigned groups
Outcomes&
estimation
17a For each primary and secondary outcome, results for
each group, and the estimated effect size and its
precision (such as 95% confidence interval)
17b For binary outcomes, presentation of both absolute and
relative effect sizes is recommended
Ancillary
analysis
18 Results of any other analyses performed, including
subgroup analyses and adjusted analyses, distinguishing
pre-specified from exploratory
harms 19 All important harms or unintended effects in each group
(for specific guidance see CONSORT for harms)
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54. Section/
Topic
Item
No
Checklist Reported
on Pg no
Discussion
Limitations 20 Trial limitations, addressing sources of potential bias,
imprecision, and, if relevant, multiplicity of analyses
Generalizabili
ty
21 Generalisability (external validity, applicability) of the
trial findings
Interpretation 22 Interpretation consistent with results, balancing benefits
and harms, and considering other relevant evidence
Other
information
Registration 23 Registration number and name of trial registry
Protocol 24 Where the full trial protocol can be accessed, if available
Funding 25 Sources of funding and other support (such as supply of
drugs), role of funders16-05-2014 68
56. References:
Textbook of Preventive and Social Medicine by K. Park
ctri.nic.in
ClinicalTrials by Stuart J Pocock
edx.org/ harvard
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